{"product_id":"combining-additional-treatments-with-surgery-for-digestive-and-pancreatic-neuroendocrine-tumors-what-patients-need-to-know","title":"Combining Additional Treatments with Surgery for Digestive and Pancreatic Neuroendocrine Tumors: What Patients Need to Know","description":"\u003cp\u003eThis review examines how additional treatments can be combined with surgery for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare group of cancers that arise in the digestive tract and pancreas. Surgery remains the main treatment, but cancer returns in many patients even after complete removal. The authors reviewed studies published between 2001 and 2026 and found that evidence for combining treatments like chemotherapy, somatostatin analogues, and peptide receptor radionuclide therapy with surgery is mostly retrospective and inconsistent. The review concludes that treatment decisions should be individualized through multidisciplinary discussion, and it identifies key areas where more research is needed.\u003c\/p\u003e\n\n\u003ch1\u003eCombining Additional Treatments with Surgery for Digestive and Pancreatic Neuroendocrine Tumors: What Patients Need to Know\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Researchers Conducted This Review\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#definition\"\u003eWhat Are GEP-NETs? Definitions and How Common They Are\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#surgery\"\u003eThe Role of Surgery\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#metastatic\"\u003eSurgery for Metastatic Disease and Symptom Relief\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#neoadjuvant-adjuvant\"\u003eNeoadjuvant vs. Adjuvant Treatment: What Is the Difference?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#chemotherapy\"\u003eChemotherapy for GEP-NETs\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#somatostatin\"\u003eSomatostatin Analogues\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What This Review Could Not Prove\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eSurgery remains the most important treatment for localized, well-differentiated GEP-NETs, but recurrence occurred in up to 48.5% of patients at 10 years in a retrospective cohort.\u003c\/li\u003e\n\u003cli\u003eEvidence for combining chemotherapy, somatostatin analogues, or peptide receptor radionuclide therapy with surgery is mostly retrospective and inconsistent, so decisions should be individualized.\u003c\/li\u003e\n\u003cli\u003eIn a meta-analysis, neoadjuvant therapy produced objective response rates of 42%, but R0 resection rates were similar with and without it (60% versus 63%).\u003c\/li\u003e\n\u003cli\u003eAdjuvant cytotoxic chemotherapy is not recommended for low- or intermediate-grade GEP-NETs, but adjuvant platinum-based chemotherapy is commonly recommended after resection of poorly differentiated neuroendocrine carcinoma.\u003c\/li\u003e\n\u003cli\u003eA European cohort study found no overall survival difference and more re-operations with prophylactic surgery (14.3%) versus delayed surgery (3.3%) in asymptomatic stage IV small bowel NETs.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eGastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a diverse group of cancers that develop from specialized hormone-producing cells in the digestive system. The number of people diagnosed with these tumors has risen steadily over recent decades.\u003c\/p\u003e\n\n\u003cp\u003eSurgery to completely remove the tumor remains the most important treatment. However, long-term follow-up studies show that the cancer returns in a substantial number of patients, both near the original site and in distant organs, even after successful surgery.\u003c\/p\u003e\n\n\u003cp\u003eMany patients also have cancer that has already spread (metastatic disease) when they are diagnosed. For these patients, surgery may still be performed to relieve symptoms, prevent complications, or remove as much tumor as possible.\u003c\/p\u003e\n\n\u003cp\u003eIn recent decades, systemic treatments for GEP-NENs have expanded significantly. These include:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eSomatostatin analogues (SSAs)\u003c\/strong\u003e — drugs that mimic a natural hormone to control tumor growth and symptoms\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eCytotoxic chemotherapy\u003c\/strong\u003e — drugs that kill cancer cells\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTargeted therapy\u003c\/strong\u003e — small-molecule inhibitors that block specific molecules involved in cancer growth\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePeptide receptor radionuclide therapy (PRRT)\u003c\/strong\u003e — a treatment that delivers radiation directly to tumor cells\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eWhile these advances have improved survival and quality of life for many patients, how best to combine them with surgery remains unclear. This review summarizes the current evidence on using additional therapies alongside surgery for GEP-NENs. The authors focus on when to use treatments before surgery (neoadjuvant), after surgery (adjuvant), and in combination with surgery to reduce tumor burden in metastatic disease.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Researchers Conducted This Review\u003c\/h2\u003e\n\n\u003cp\u003eThe authors performed a targeted narrative literature search in PubMed\/MEDLINE, a major medical research database. They searched for studies published between 2001 and 2026. They also searched ClinicalTrials.gov and major medical society guidelines.\u003c\/p\u003e\n\n\u003cp\u003eThe search terms included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\"Gastroenteropancreatic neuroendocrine tumor\" and \"GEP-NET\"\u003c\/li\u003e\n\u003cli\u003e\"Pancreatic neuroendocrine tumor\"\u003c\/li\u003e\n\u003cli\u003e\"Surgery\" and \"palliative surgery\"\u003c\/li\u003e\n\u003cli\u003e\"Neoadjuvant\" and \"adjuvant\"\u003c\/li\u003e\n\u003cli\u003e\"PRRT\" and \"somatostatin analogue\"\u003c\/li\u003e\n\u003cli\u003e\"Chemotherapy,\" \"targeted therapy,\" and \"immune checkpoint inhibitor\"\u003c\/li\u003e\n\u003cli\u003e\"Liver-directed therapy\"\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe search covered publications from January 2001 to July 2026. No language restriction was applied, but only English-language manuscripts were ultimately reviewed.\u003c\/p\u003e\n\n\u003cp\u003eEligible study designs included randomized controlled trials (RCTs), prospective or retrospective cohort studies, case-control studies, and meta-analyses that reported data specific to the time around surgery. The authors also hand-searched the bibliographies of retrieved articles and relevant international guidelines from ENETS, NANETS, NCCN, and ESMO to identify additional eligible studies.\u003c\/p\u003e\n\n\u003cp\u003eStudies were included if they reported outcomes in the perioperative context, defined as data specifically pertaining to the neoadjuvant, adjuvant, or intraoperative setting. Studies reporting exclusively on patients with advanced, inoperable, or metastatic disease without a surgical component were excluded from the perioperative subsections. However, these studies are referenced in the general overview to provide context about how treatments work and how effective they are.\u003c\/p\u003e\n\n\u003cp\u003eRetrospective studies with fewer than 10 patients in the perioperative group were also excluded to minimize reporting bias. This review is narrative in design. Although a systematic search strategy was employed to maximize retrieval of literature, no formal screening flowchart was produced. The synthesis reflects the authors' critical appraisal rather than a systematic protocol.\u003c\/p\u003e\n\n\u003cp\u003eEvidence from advanced disease and landmark trials (such as NETTER, PROMID, and CLARINET) is presented in the general overview to establish biological plausibility and treatment context. However, these results are clearly distinguished from evidence derived specifically from the time around surgery.\u003c\/p\u003e\n\n\u003ch2 id=\"definition\"\u003eWhat Are GEP-NETs? Definitions and How Common They Are\u003c\/h2\u003e\n\n\u003cp\u003eNeuroendocrine tumors (NETs) are heterogeneous tumors that arise from secretory cells of the neuroendocrine system. These include well-differentiated neuroendocrine tumors (NETs, grades G1-G3) and poorly differentiated neuroendocrine carcinomas (NECs), which are biologically and clinically distinct entities.\u003c\/p\u003e\n\n\u003cp\u003eFor clarity, the term GEP-NET is used throughout this review to refer to well-differentiated tumors. GEP-NEC refers specifically to poorly differentiated carcinomas. The broader term GEP-NEN is used when both groups are addressed together.\u003c\/p\u003e\n\n\u003cp\u003eGEP-NETs arise from the gastrointestinal tract and pancreas. They may be functional (producing hormones that cause symptoms) or non-functional. They are most frequently found in:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eSmall intestine: 30.8% of cases\u003c\/li\u003e\n\u003cli\u003eRectum: 26.3% of cases\u003c\/li\u003e\n\u003cli\u003eColon: 17.6% of cases\u003c\/li\u003e\n\u003cli\u003ePancreas: 12.1% of cases\u003c\/li\u003e\n\u003cli\u003eAppendix: 5.7% of cases\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eWith diagnostic advancements, the age-adjusted annual incidence of GEP-NETs has increased from 1.09 to 6.98 per 100,000 persons over the last 40 years. This increase is partly due to the widespread use of imaging studies. This underscores the need for continued research and optimized treatment strategies.\u003c\/p\u003e\n\n\u003ch2 id=\"surgery\"\u003eThe Role of Surgery\u003c\/h2\u003e\n\n\u003cp\u003eSurgery remains the cornerstone of treatment for most patients with well-differentiated G1-G2 tumors and selected patients with G3 disease. Surgery can result in long-term survival and symptom control in functional tumors.\u003c\/p\u003e\n\n\u003cp\u003eIn a large retrospective cohort of 936 patients undergoing a first curative-intent resection of a GEP-NET, overall survival was:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e92.2% at 3 years\u003c\/li\u003e\n\u003cli\u003e85.3% at 5 years\u003c\/li\u003e\n\u003cli\u003e68.1% at 10 years\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eHowever, recurrence remains common, occurring in up to 48.5% of patients at 10 years.\u003c\/p\u003e\n\n\u003cp\u003eFor localized disease, surgical principles vary by primary site but consistently aim to achieve complete (R0) resection, meaning no cancer cells are left behind at the margins.\u003c\/p\u003e\n\n\u003cp\u003eIn small bowel NETs, segmental resection with en bloc mesenteric lymphadenectomy (removal of lymph nodes in the tissue surrounding the intestine) and careful intraoperative evaluation for multifocal disease is critical.\u003c\/p\u003e\n\n\u003cp\u003eIn pancreatic NETs (pNETs), resection or enucleation (removing just the tumor while preserving surrounding tissue) is generally recommended when tumors are functioning and\/or 2 cm or larger. Active surveillance is appropriate for small (less than 2 cm), non-functioning pancreatic NETs.\u003c\/p\u003e\n\n\u003cp\u003eFor gastric and colorectal NETs, management is more size- and risk-dependent. Smaller, low-grade lesions are often amenable to endoscopic resection. Larger or higher-risk tumors require anatomical resection with lymphadenectomy.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, while R0 resection remains the goal, margin status appears to have a greater impact on recurrence than on overall survival. Re-resection to achieve negative margins has not been shown to improve outcomes. This supports the use of parenchyma- or organ-preserving approaches when feasible.\u003c\/p\u003e\n\n\u003cp\u003eWhile surgery is recommended for patients with resectable disease, additional factors to consider prior to operative intervention include functional NETs that require symptom control and selected patients with metastatic disease.\u003c\/p\u003e\n\n\u003cp\u003eTumor biology and grade are some of the most important considerations. For example, some societies, such as the North American Neuroendocrine Tumor Society (NANETS), caution against routine surgical resection for poorly differentiated tumors such as neuroendocrine carcinoma (NEC). This caution is due to a lack of convincing data demonstrating a survival benefit.\u003c\/p\u003e\n\n\u003cp\u003eWhile resection may be needed for symptom control, patients should be optimized prior to proceeding with resection. This is particularly important for those with carcinoid syndrome, given the increased perioperative risk.\u003c\/p\u003e\n\n\u003cp\u003eFinally, patient comorbidities (other medical conditions) and overall expected life expectancy, as well as any underlying hereditary syndrome, should also be considered. In hereditary syndromes, it is particularly essential to consider the likelihood of recurrence and the need for possible repeated organ resection. In these cases, a parenchymal-sparing resection should be employed when feasible. Observation over resection may even be advisable.\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, patients with hereditary syndromes may harbor other associated malignancies that require surgical management. This can further influence the timing and sequencing of operative interventions.\u003c\/p\u003e\n\n\u003cp\u003eIt should be noted that the role of surgery in G3 and NEC is controversial with little consensus between society guidelines. Presently, the European Neuroendocrine Tumor Society (ENETS), the National Comprehensive Cancer Network (NCCN), and the European Society of Medical Oncology (ESMO) guidelines recommend consideration for surgical resection. This recommendation applies to GEP-NET G3 and GEP-NEC when feasible. NANETS does not recommend upfront surgery.\u003c\/p\u003e\n\n\u003cp\u003eWhile there is consensus among societies that surgery should be avoided in patients with metastatic or locally advanced NECs, the role of surgery for resectable NECs is controversial. It should be used selectively after a discussion in a multidisciplinary conference.\u003c\/p\u003e\n\n\u003cp\u003eTo help guide surgical management and surveillance following resection, several groups have developed recurrence-risk models for GEP-NETs.\u003c\/p\u003e\n\n\u003cp\u003eIn one multicenter study of 1,006 pNETs, symptoms, tumor size, Ki-67 (a marker of how fast cancer cells are dividing), and nodal status were used to stratify patients into low-, intermediate-, and high-risk recurrence groups. Each group had distinct recommended surveillance intervals.\u003c\/p\u003e\n\n\u003cp\u003eSimilarly, a retrospective review of patients with localized pNETs found that lymph node involvement, histologic grade, tumor size, and Ki-67 were independent predictors of post-resection metastatic recurrence.\u003c\/p\u003e\n\n\u003cp\u003eA second retrospective study of 441 GEP-NETs developed a prognostic score to determine recurrence risk in patients following curative-intent resection. This score included TNM stage, lymph node ratio, and margin status. The study found significant differences in recurrence-free survival (RFS) between low-, medium-, and high-risk patients. This demonstrates the importance of a patient-specific surveillance strategy following surgical resection.\u003c\/p\u003e\n\n\u003cp\u003eAdditional markers, including the neutrophil-to-lymphocyte ratio (NLR), have also been found in the preoperative setting to correlate with tumor stage, lymph node metastasis, and tumor grade. These offer complementary tools for risk stratification prior to resection.\u003c\/p\u003e\n\n\u003cp\u003eSurgery for GEP-NETs is generally safe with very low reported rates of perioperative mortality. The morbidity (complications) associated with resection of GEP-NETs, however, is non-negligible, organ-specific, and should be considered along with other patient risk factors in determining appropriateness for resection.\u003c\/p\u003e\n\n\u003cp\u003eSmall bowel NET resections have associated morbidity in approximately 13% of cases. The most common complications include intraabdominal bleeding and ileus (a temporary lack of bowel movement).\u003c\/p\u003e\n\n\u003cp\u003ePancreatic resections or enucleations, however, have a much higher associated morbidity. A systematic review of the literature reported postoperative morbidity in approximately 50% of pancreatic enucleations for all indications. The most common complication was a postoperative pancreatic fistula (POPF), which is a leak of pancreatic fluid.\u003c\/p\u003e\n\n\u003cp\u003eWhen looking at all pancreatic enucleations, the POPF rate was higher in patients with pNETs compared to enucleation for other causes. This emphasizes the particular risk in this patient population.\u003c\/p\u003e\n\n\u003cp\u003eDespite the morbidity risk associated with parenchymal-sparing procedures, complication rates are higher still in patients undergoing pancreatic resection for pNETs, with reported POPF rates of up to 58%. Other common complications following pancreatic resection for pNETs included delayed gastric emptying and postoperative hemorrhage.\u003c\/p\u003e\n\n\u003ch2 id=\"metastatic\"\u003eSurgery for Metastatic Disease and Symptom Relief\u003c\/h2\u003e\n\n\u003cp\u003eWhile approximately 50% of patients with GEP-NENs initially present with localized disease, there is no definitive data on the percentage of patients with GEP-NENs initially presenting with resectable disease. Up to 27% of patients present with distant metastases at the time of diagnosis. This underscores the importance of considering surgical management, including metastasectomy (surgical removal of metastases), in select individuals.\u003c\/p\u003e\n\n\u003cp\u003eThe liver is the most common site of GEP-NEN metastases, followed by regional lymph nodes and less commonly bone, lungs, and peritoneum. Liver metastases are associated with worse constitutional symptoms and overall survival.\u003c\/p\u003e\n\n\u003cp\u003eAs such, patients with metastatic disease may be eligible for surgical interventions to control symptoms or prolong survival. In a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database, primary resection with metastasectomy was associated with longer disease-specific survival compared to no surgery. Furthermore, metastasectomy has been associated with prolonged survival in patients with recurrent liver metastases. However, these retrospective analyses are inevitably confounded by selection bias.\u003c\/p\u003e\n\n\u003cp\u003eWhile resection of the primary tumor in patients with metastatic GEP-NETs may be controversial, it is recommended for symptomatic management when feasible. Additionally, primary small bowel NETs are typically recommended for resection due to the risk of obstruction even in the presence of distant metastasis.\u003c\/p\u003e\n\n\u003cp\u003ePalliative surgery may also be required to either treat or prevent bowel obstructions or manage symptoms related to carcinoid syndrome. However, it remains debatable whether such prophylactic surgery is necessary to prevent complications.\u003c\/p\u003e\n\n\u003cp\u003eA retrospective review of patients who underwent surgery for small bowel NETs found that emergency resections were required in approximately 8% of cases for obstruction or perforation.\u003c\/p\u003e\n\n\u003cp\u003eA European cohort study of asymptomatic patients with stage IV small bowel NETs attempted to answer the question of whether early surgical intervention could prevent complications. The group compared patients who underwent prophylactic resection for small bowel NETs within six months of diagnosis, in addition to oncologic therapy. The group compared these patients to those who were managed with oncologic therapy alone or delayed surgery.\u003c\/p\u003e\n\n\u003cp\u003eThe authors found that there was no difference in overall survival. Furthermore, patients in the prophylactic surgery group had more re-operative procedures (14.3%) compared to those in the delayed surgery group (3.3%). This suggests that prophylactic surgery for stage IV small bowel NETs may not be beneficial.\u003c\/p\u003e\n\n\u003ch2 id=\"neoadjuvant-adjuvant\"\u003eNeoadjuvant vs. Adjuvant Treatment: What Is the Difference?\u003c\/h2\u003e\n\n\u003cp\u003eAdjunct therapies may complement surgery in selected patients. However, most available evidence is retrospective and heterogeneous, limiting clear conclusions regarding their optimal use.\u003c\/p\u003e\n\n\u003cp\u003eFor the purposes of this review, the following definitions are applied consistently:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eNeoadjuvant therapy\u003c\/strong\u003e refers to systemic or liver-directed treatment administered prior to planned surgical resection with the intent to downstage disease or improve resectability.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAdjuvant therapy\u003c\/strong\u003e refers to treatment administered after curative-intent resection in patients with no clinical evidence of residual disease, with the goal of reducing recurrence risk.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSalvage therapy\u003c\/strong\u003e refers to treatment initiation at the time of confirmed disease recurrence or progression following prior resection.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese distinctions are particularly important given that evidence quality and clinical applicability differ substantially across these settings.\u003c\/p\u003e\n\n\u003cp\u003eThe current guidelines (ENETS, NANETS, NCCN, ESMO, ASCO) do not routinely recommend adjuvant therapy after R0 or R1 resection of well-differentiated GEP-NETs. However, this gap in knowledge is currently being studied in clinical trials (NCT05040360). In addition, it is not uncommon to start or continue somatostatin analogues (SSAs) in patients with residual tumors. Thus, the use of adjunct therapy in patients with resectable, well-differentiated GEP-NETs should be personalized and discussed in a multidisciplinary tumor board.\u003c\/p\u003e\n\n\u003cp\u003eIn poorly differentiated NEC, adjuvant platinum-based chemotherapy is commonly recommended despite the absence of randomized trials.\u003c\/p\u003e\n\n\u003cp\u003eNeoadjuvant therapy may help downstage and improve resectability in locally advanced GEP-NETs, although this effect is not uniformly seen. A systematic review and meta-analysis assessed the role of neoadjuvant therapy in GEP-NETs. Neoadjuvant therapy includes PRRT, chemotherapy, and sunitinib. The review found that neoadjuvant therapy may be effective and safe in the treatment of GEP-NETs. Authors reported objective response rates (ORR) of 42%.\u003c\/p\u003e\n\n\u003cp\u003eInterestingly, in this same study, the R0 resection rates for patients were similar between those who received neoadjuvant treatment and those who did not (60% vs. 63%). This indicates that neoadjuvant therapy was not associated with an increase in R0 resection.\u003c\/p\u003e\n\n\u003cp\u003eThe goals of postoperative adjuvant therapy include:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003eReduction in locoregional and\/or systemic disease recurrence following R0 resection in patients who are at risk for microscopic metastatic or residual disease.\u003c\/li\u003e\n\u003cli\u003eIncrease in progression-free survival in patients who underwent cytoreduction with clinically detectable residual disease.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThere is an absence of level I evidence of clinical benefits, with some conflicting evidence. The use of adjuvant therapy in patients with GEP-NETs undergoing surgery should be individualized based on the risk of disease progression.\u003c\/p\u003e\n\n\u003cp\u003eA retrospective study from US-NETSG did not find any differences in OS and RFS in patients with primary GEP-NETs who underwent curative-intent resection. The study compared those who received adjuvant cytotoxic chemotherapy or SSAs to those who did not.\u003c\/p\u003e\n\n\u003cp\u003eAdditionally, a retrospective review of the National Cancer Database (NCD) compared the benefit of perioperative systemic therapy to surgery alone. The review examined patients undergoing curative-intent resection of localized pNETs. The review found no difference in overall survival (OS).\u003c\/p\u003e\n\n\u003cp\u003eRisk stratification using clinical variables such as tumor grade, tumor burden, and pace of disease progression should therefore guide individualized treatment decisions. While postoperative adjuvant therapy aims to improve disease progression only after surgery, the additional goal of neoadjuvant therapy is to improve resectability in patients with unresectable or borderline resectable disease.\u003c\/p\u003e\n\n\u003cp\u003eRegarding NEC or high-grade GEP-NETs, the data and recommendations for the use of neoadjuvant therapy are not universally accepted. Presently, neoadjuvant therapy is not recommended for the treatment of NEC in the Nordic guidelines, whereas other societies recommend multidisciplinary consideration for its use in poorly differentiated tumors.\u003c\/p\u003e\n\n\u003ch2 id=\"chemotherapy\"\u003eChemotherapy for GEP-NETs\u003c\/h2\u003e\n\n\u003cp\u003eCytotoxic chemotherapy is used to treat GEP-NETs with rapid disease progression, primarily in the treatment of grade 3 GEP-NETs.\u003c\/p\u003e\n\n\u003cp\u003eThe combination of temozolomide and capecitabine (CAPTEM) has demonstrated efficacy in treating GEP-NETs. It has shown objective response rates ranging between 30-70% and a significantly longer progression-free survival (PFS) compared to temozolomide alone in pNETs specifically.\u003c\/p\u003e\n\n\u003cp\u003eIn one retrospective review from Columbia University, Fine et al. report an objective response rate of 61% for patients with metastatic GEP-NETs to the liver.\u003c\/p\u003e\n\n\u003cp\u003eDacarbazine, when combined with 5-fluorouracil (5-FU), represents an alternative to CAPTEM. It has demonstrated similar efficacy in advanced GEP-NETs, with reported objective response rates of approximately 38-39%.\u003c\/p\u003e\n\n\u003cp\u003eStreptozocin-based regimens have also been used in the treatment of pNETs, particularly in combination with other cytotoxic agents or antiangiogenic agents.\u003c\/p\u003e\n\n\u003cp\u003ePrakash et al. (2017) retrospectively assessed response rates in patients with localized pNETs who received neoadjuvant 5-FU, doxorubicin, and streptozotocin. The authors found that 90% of patients had stable disease (SD). This is compared to 7% who had a partial response (PR) and 3% who had progression of disease (PD). These responses were as defined by the Response Evaluation Criteria in Solid Tumors (RECIST).\u003c\/p\u003e\n\n\u003cp\u003eFOLFOX has also demonstrated some efficacy in the treatment of advanced GEP-NETs. According to one retrospective series, reported rates of disease control were 75% of all cases. The reported rate was 91.3% when FOLFOX was used as a first-line treatment. Additionally, FOLFOX has also demonstrated efficacy in well-differentiated metastatic pNETs that have progressed on prior therapy, with reported overall response rates of 45.2%.\u003c\/p\u003e\n\n\u003cp\u003eRegimens for NEC include platinum-based chemotherapy in addition to etoposide. Additionally, folinic acid, fluorouracil, and irinotecan (FOLFIRI) and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) have demonstrated some marginal benefit. This benefit is for patients with metastatic or localized NEC who have progressed on platinum regimens.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eNeoadjuvant Chemotherapy\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eChemotherapy has also been used in the neoadjuvant setting. A single-center retrospective review in patients with pNETs and borderline resectable disease demonstrated successful surgical resection following neoadjuvant CAPTEM with or without radiation.\u003c\/p\u003e\n\n\u003cp\u003eCAPTEM was further validated in another retrospective review in which patients with locally advanced or resectable metastatic pNETs were treated with neoadjuvant CAPTEM. The authors found that 43% of patients exhibited a partial radiographic response and 87% underwent resection. They reported a median PFS of 28.2 months and 5-year OS of 63%. This suggests that CAPTEM may be useful in the neoadjuvant setting for patients with borderline resectable or metastatic pNETs.\u003c\/p\u003e\n\n\u003cp\u003eThe combination of chemotherapy with other modalities has also demonstrated some efficacy in the neoadjuvant setting. A retrospective review of patients with GEP-NETs initially treated with combination oxaliplatin-fluoropyrimidine chemotherapy and SSA reported a disease control rate of 87.5%. In this study, 28% of patients demonstrated downstaging to radiographic resectability, highlighting the potential utility of chemotherapy in the neoadjuvant setting.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAdjuvant Chemotherapy\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eRegarding standard cytotoxic chemotherapy, adjuvant treatment is not recommended in low- or intermediate-grade GEP-NETs, given low recurrence rates and a lack of data supporting any benefit of postoperative therapy.\u003c\/p\u003e\n\n\u003cp\u003eA retrospective review assessed the efficacy of adjuvant streptozotocin and 5-FU following resection of liver metastasis for GEP-NETs. The study found no statistically different significance in RFS or OS between those that received adjuvant chemotherapy and those that did not (RFS at 5 years 20% vs. 38%, p=0.36; OS at 5 years 96% vs. 76%, p=0.58).\u003c\/p\u003e\n\n\u003cp\u003eHowever, adjuvant chemotherapy is commonly recommended following resection in patients with NECs, given the high risk of recurrence and systemic metastasis following resection. This recommendation exists despite a lack of randomized controlled trials demonstrating their benefit. Given that surgery is rarely curative for patients with NEC, adjuvant treatment with platinum and etoposide should be considered after surgery due to the high risk of recurrence.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinical Implication:\u003c\/strong\u003e CAPTEM-based neoadjuvant chemotherapy may be considered in selected patients with borderline resectable or locally advanced pNETs. Adjuvant cytotoxic chemotherapy is not recommended for well-differentiated GEP-NETs but is a standard consideration following resection of NEC. FOLFOX\/XELOX remains investigational in the perioperative setting.\u003c\/p\u003e\n\n\u003ch2 id=\"somatostatin\"\u003eSomatostatin Analogues\u003c\/h2\u003e\n\n\u003cp\u003eFor patients with advanced or unresectable functional GEP-NETs, SSAs are the standard first-line treatment. The PROMID trial was a double-blind, placebo-controlled study that demonstrated the efficacy of octreotide in patients with midgut NETs.\u003c\/p\u003e\n\n\u003cp\u003eSSAs work by mimicking somatostatin, a natural hormone in the body that regulates hormone secretion and cell growth. By binding to somatostatin receptors on tumor cells, these drugs can slow tumor growth and control symptoms caused by excess hormone production.\u003c\/p\u003e\n\n\u003cp\u003eIn the perioperative setting, SSAs may be used in several ways:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eTo control symptoms in patients with functional tumors before surgery\u003c\/li\u003e\n\u003cli\u003eTo prevent carcinoid crisis (a dangerous surge of hormones) during surgery\u003c\/li\u003e\n\u003cli\u003eTo continue treatment in patients with residual tumor after surgery\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe review notes that it is not uncommon to start or continue SSAs in patients with residual tumors after surgery. However, the evidence for this practice is not strong, and the decision should be made on an individual basis through multidisciplinary discussion.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe evidence reviewed here has several important implications for patients with GEP-NETs.\u003c\/p\u003e\n\n\u003cp\u003eFirst, surgery remains the most important treatment for patients with localized, well-differentiated GEP-NETs. Complete removal of the tumor offers the best chance for long-term survival. However, patients should be aware that recurrence is common, occurring in up to 48.5% of patients at 10 years, even after successful surgery.\u003c\/p\u003e\n\n\u003cp\u003eSecond, the decision to use additional treatments before or after surgery should be individualized. There is no single approach that works for all patients. Factors such as tumor grade, tumor size, lymph node involvement, and the pace of disease progression should guide these decisions.\u003c\/p\u003e\n\n\u003cp\u003eThird, for patients with borderline resectable or locally advanced pancreatic NETs, neoadjuvant chemotherapy with CAPTEM may be considered. This approach has shown objective response rates of 30-70% and may help make surgery possible. However, it is important to note that neoadjuvant therapy has not been consistently shown to increase the rate of complete (R0) resection.\u003c\/p\u003e\n\n\u003cp\u003eFourth, for patients with poorly differentiated neuroendocrine carcinoma (NEC), adjuvant platinum-based chemotherapy is commonly recommended after surgery. This is despite the absence of randomized trials demonstrating a benefit, because the risk of recurrence is very high.\u003c\/p\u003e\n\n\u003cp\u003eFifth, for patients with metastatic disease, surgery may still play a role in controlling symptoms, preventing complications, and potentially prolonging survival. However, the decision to perform surgery in this setting should be made carefully, considering the risks and benefits for each patient.\u003c\/p\u003e\n\n\u003cp\u003eFinally, the review emphasizes that management of GEP-NETs should be individualized through multidisciplinary discussion. This means that a team of specialists, including surgeons, medical oncologists, and other experts, should work together to develop a treatment plan that is tailored to each patient's specific situation.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What This Review Could Not Prove\u003c\/h2\u003e\n\n\u003cp\u003eThe authors acknowledge several important limitations of this review and the evidence it summarizes.\u003c\/p\u003e\n\n\u003cp\u003eFirst, the overall evidence base for adjunct therapies with surgery in GEP-NETs is largely retrospective and heterogeneous. This means that most studies look back at patient records rather than randomly assigning patients to different treatments. Retrospective studies are subject to selection bias, meaning that patients who received certain treatments may have been different from those who did not in ways that affect outcomes.\u003c\/p\u003e\n\n\u003cp\u003eSecond, there is a lack of high-quality prospective evidence, such as randomized controlled trials, in the perioperative setting. This makes it difficult to draw firm conclusions about the benefits of neoadjuvant or adjuvant therapy.\u003c\/p\u003e\n\n\u003cp\u003eThird, the review is narrative in design rather than systematic. Although a systematic search strategy was employed, no formal screening flowchart was produced. The synthesis reflects the authors' critical appraisal rather than a systematic protocol.\u003c\/p\u003e\n\n\u003cp\u003eFourth, the R0 resection rates are inconsistent across different treatment modalities. For example, in one meta-analysis, the R0 resection rates were similar between patients who received neoadjuvant treatment and those who did not (60% vs. 63%). This suggests that neoadjuvant therapy may not always improve the ability to completely remove the tumor.\u003c\/p\u003e\n\n\u003cp\u003eFifth, there is no definitive data on the percentage of patients with GEP-NENs who initially present with resectable disease. This makes it difficult to estimate how many patients might benefit from surgery.\u003c\/p\u003e\n\n\u003cp\u003eSixth, the role of surgery in G3 and NEC is controversial, with little consensus between society guidelines. Some societies recommend consideration for surgical resection, while others do not recommend upfront surgery.\u003c\/p\u003e\n\n\u003cp\u003eFinally, the review notes that the evidence for prophylactic surgery in asymptomatic patients with stage IV small bowel NETs suggests that this approach may not be beneficial. A European cohort study found no difference in overall survival and more re-operative procedures in the prophylactic surgery group (14.3%) compared to the delayed surgery group (3.3%).\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003cp\u003eBased on this review, patients with GEP-NETs should consider the following recommendations:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eSeek care at a specialized center.\u003c\/strong\u003e GEP-NETs are rare and complex tumors. Treatment at a center with expertise in neuroendocrine tumors can help ensure that you receive the most appropriate care.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscuss your case in a multidisciplinary tumor board.\u003c\/strong\u003e The review emphasizes that management should be individualized through multidisciplinary discussion. Ask your care team whether your case has been reviewed by a team of specialists.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnderstand your tumor grade and stage.\u003c\/strong\u003e Tumor grade (G1, G2, G3, or NEC) and stage are important factors in determining the best treatment approach. Ask your doctor to explain these in detail.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk about clinical trials.\u003c\/strong\u003e The review notes that there is a gap in knowledge about the optimal use of adjunct therapies with surgery. Clinical trials are currently studying this question (NCT05040360). Ask your doctor whether you might be eligible for a clinical trial.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBe aware of the risks and benefits of surgery.\u003c\/strong\u003e Surgery for GEP-NETs is generally safe with very low rates of perioperative mortality. However, complications are possible and vary depending on the type of surgery. Discuss these risks with your surgeon.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnderstand the role of additional treatments.\u003c\/strong\u003e Neoadjuvant therapy (before surgery) may help downstage tumors and improve resectability in some patients. Adjuvant therapy (after surgery) is not routinely recommended for well-differentiated GEP-NETs but is commonly recommended for NEC.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eConsider a parenchymal-sparing approach when feasible.\u003c\/strong\u003e For patients with hereditary syndromes or those who may need repeated organ resection, preserving as much healthy tissue as possible is important.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFollow up regularly.\u003c\/strong\u003e Recurrence is common even after successful surgery. Regular surveillance can help detect recurrence early, when it may be more treatable.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat are GEP-NETs and how common are they?\u003c\/h3\u003e\n\u003cp\u003eGEP-NETs are well-differentiated neuroendocrine tumors arising in the digestive tract and pancreas. They are most often found in the small intestine (30.8%), rectum (26.3%), colon (17.6%), pancreas (12.1%), and appendix (5.7%). The age-adjusted annual incidence has risen from 1.09 to 6.98 per 100,000 persons over the last 40 years, partly due to wider use of imaging studies.\u003c\/p\u003e\n\u003ch3\u003eWhat is the difference between neoadjuvant and adjuvant treatment?\u003c\/h3\u003e\n\u003cp\u003eNeoadjuvant therapy is systemic or liver-directed treatment given before planned surgical resection, aiming to downstage disease or improve resectability. Adjuvant therapy is given after curative-intent resection when there is no clinical evidence of residual disease, aiming to reduce recurrence risk. Salvage therapy is started at confirmed recurrence or progression after prior resection. Guidelines do not routinely recommend adjuvant therapy after R0 or R1 resection of well-differentiated GEP-NETs.\u003c\/p\u003e\n\u003ch3\u003eWhat are the risks and recovery after surgery for GEP-NETs?\u003c\/h3\u003e\n\u003cp\u003eSurgery for GEP-NETs is generally safe with very low reported perioperative mortality, but complications are possible and vary by operation. Small bowel NET resection has morbidity in about 13% of cases, most commonly intraabdominal bleeding and ileus. Pancreatic enucleation has morbidity in about 50% of cases, most often postoperative pancreatic fistula, and pancreatic resection has reported fistula rates up to 58%.\u003c\/p\u003e\n\u003ch3\u003eCan additional treatments before surgery make an inoperable tumor removable?\u003c\/h3\u003e\n\u003cp\u003eNeoadjuvant therapy may help downstage and improve resectability in locally advanced GEP-NETs, although this effect is not uniformly seen. A systematic review and meta-analysis reported objective response rates of 42%, but R0 resection rates were similar between patients who received neoadjuvant treatment and those who did not (60% versus 63%). This suggests neoadjuvant therapy was not associated with an increase in complete resection.\u003c\/p\u003e\n\u003ch3\u003eIs adjuvant chemotherapy recommended after surgery for GEP-NETs?\u003c\/h3\u003e\n\u003cp\u003eAdjuvant cytotoxic chemotherapy is not recommended for low- or intermediate-grade GEP-NETs, given low recurrence rates and a lack of data supporting benefit. A retrospective review found no statistically significant difference in recurrence-free or overall survival after resection of liver metastasis between those who received adjuvant streptozotocin and 5-FU and those who did not. However, adjuvant platinum-based chemotherapy is commonly recommended after resection of poorly differentiated neuroendocrine carcinoma.\u003c\/p\u003e\n\u003ch3\u003eWhat should patients ask their care team about treatment decisions?\u003c\/h3\u003e\n\u003cp\u003eAsk whether your case has been reviewed by a multidisciplinary tumor board, since management should be individualized through multidisciplinary discussion. Ask your doctor to explain your tumor grade and stage in detail, and whether you might be eligible for a clinical trial; one trial is studying adjuvant therapy after resection (NCT05040360). Also discuss the risks and benefits of your specific surgery and a regular surveillance plan, because recurrence is common even after successful surgery.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with a digestive or pancreatic neuroendocrine tumor seek a second opinion about combining treatments with surgery?\u003c\/h3\u003e\n\u003cp\u003eBecause evidence for combining chemotherapy, somatostatin analogues, or peptide receptor radionuclide therapy with surgery is mostly retrospective and inconsistent, and guidelines do not routinely recommend adjuvant therapy after complete removal of well-differentiated tumors, treatment decisions should be individualized through multidisciplinary discussion. A second opinion can help confirm tumor grade and stage, clarify whether neoadjuvant or adjuvant treatment is appropriate, and identify clinical trials. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal Article Title:\u003c\/strong\u003e The Use of Adjunct Therapies with Surgery for Gastroenteropancreatic Neuroendocrine Tumors: Indications, Timing, and Outcomes.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eJournal:\u003c\/strong\u003e Biomedicines\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eLicense:\u003c\/strong\u003e CC BY (open access)\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Cavallo K, Nilubol N.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor Affiliations:\u003c\/strong\u003e Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Biomedicines 2026, 14, 2105\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e https:\/\/doi.org\/10.3390\/biomedicines14092105\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication Date:\u003c\/strong\u003e September 18, 2026\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eNote:\u003c\/strong\u003e This patient-friendly article is based on peer-reviewed research. The original article is a narrative review that synthesizes available evidence on the role of perioperative therapies in the surgical management of gastroenteropancreatic neuroendocrine neoplasms. The review identifies key knowledge gaps and highlights areas where multidisciplinary decision-making is required.\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47816854241436,"sku":null,"price":0.0,"currency_code":"KRW","in_stock":true}],"url":"https:\/\/diagnosticdetectives.kr\/products\/combining-additional-treatments-with-surgery-for-digestive-and-pancreatic-neuroendocrine-tumors-what-patients-need-to-know","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}